Common features of autoimmune diseases are the presence of polyclonal gammopathy, the presence of cells secreting "spontaneously" antibody against various antigens and the presence of autoantibodies. The same features can be artificially created in vitro when normal B cells are stimulated by polyclonal B cell activators (PBA). Therefore, we determined whether PBA is present in the serum of patients with autoimmune diseases. Two methods were used: 1) the maintenance only in the presence of PBA of surface Ig of rabbit or human B lymphocytes in culture and 2) the induction of blast transformation in cultures of human B cells or nude mouse spleen cells. PBA was detected in the serum of 52 out of 57 patients with rheumatoid arthritis or related autoimmune diseases but in none of the 19 normal individuals or 10 patients with "non-autoimmune" arthritis. The entire PBA activity of the patient serum was found associated with the Alpha2 macroglobulin (AlphaM); normal AlphaM had no PBA activity. The PBA was induced in rabbits by i.v. inoculation of phytohemagglutinin, BCG, sheep erythrocytes or allogeneic cells and the entire PBA acitivity was associated with AlphaM. To demonstrate the cellular origin of this PBA, we investigated the autologous mixed lymphocyte reactions. We found that upon close contact B cells stimulate T cells to produce an Alpha2M with PBA activity. Our results strongly suggest that this PBA is the helper factor in antibody formation. Based on these observations, we propose: 1) to study the clinical value of testing for PBA in patient serum; 2) to determine the kinetics of PBA formation in the serum of experimental animals and in patients with acute infections; 3) to demonstrate polyclonal antibody formation in vitro using Alpha2M from patients; 4) to demonstrate the production of Alpha2M in human lymphocyte cultures and 5) to determine the nature of the difference between the Alpha2M produced in the liver and that produced by T cells. The results of this investigation may lead to a new diagnostic test, to the elucidation of the mechanism of T-B cell collaboration, to a new explanation for increased incidence of lymphoma-leukemia in patients with rheumatoid arthritis and possibly to new therapeutic approaches.